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Biol Psychiatry DOI:10.1016/j.biopsych.2013.12.018

The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function.

Publication TypeJournal Article
Year of Publication2014
AuthorsSmoller, JW, Gallagher, PJ, Duncan, LE, McGrath, LM, Haddad, SA, Holmes, AJ, Wolf, AB, Hilker, S, Block, SR, Weill, S, Young, S, Choi, EYoung, Rosenbaum, JF, Biederman, J, Faraone, SV, Roffman, JL, Manfro, GG, Blaya, C, Hirshfeld-Becker, DR, Stein, MB, Van Ameringen, M, Tolin, DF, Otto, MW, Pollack, MH, Simon, NM, Buckner, RL, Öngür, D, Cohen, BM
JournalBiol Psychiatry
Date Published2014 Dec 01
KeywordsAcid Sensing Ion Channels, Adult, Amygdala, Brain Mapping, Case-Control Studies, Female, Genetic Association Studies, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Panic Disorder, Polymorphism, Single Nucleotide

BACKGROUND: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function.

METHODS: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals.

RESULTS: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048).

CONCLUSIONS: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.


Alternate JournalBiol. Psychiatry
PubMed ID24529281
PubMed Central IDPMC4103972
Grant ListK24 MH094614 / MH / NIMH NIH HHS / United States
R01 47077 / / PHS HHS / United States
K24MH094614 / MH / NIMH NIH HHS / United States
T32-MH16259 / MH / NIMH NIH HHS / United States
R01 MH081116 / MH / NIMH NIH HHS / United States
K24 MH064122 / MH / NIMH NIH HHS / United States
MH64122 / MH / NIMH NIH HHS / United States
K01 MH099232 / MH / NIMH NIH HHS / United States
T32MH017119 / MH / NIMH NIH HHS / United States
T32 MH017119 / MH / NIMH NIH HHS / United States
R01 63683 / / PHS HHS / United States
T32 MH016259 / MH / NIMH NIH HHS / United States